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Updated: Mar 27, 2026
Impact of Intracardiac Neurons on Cardiac Electrophysiology and Arrhythmogenesis in an Ex Vivo Langendorff System
Published on: May 22, 2018
Preserved Autonomic Cardiovascular Regulation With Cardiac Pacemaker Inhibition: A Crossover Trial Using
Karsten Heusser1, Jens Tank1, Julia Brinkmann1
1Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany (K.H., J.T., J.B., C.S., M.M., J.J.).
Insights
Ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) blocker, effectively lowers heart rate (HR) without impacting blood pressure or sympathetic nerve activity. However, it may worsen bradycardia during parasympathetic activation.
Area of Science:
- Cardiovascular Physiology
- Autonomic Nervous System Regulation
- Pharmacology
Background:
- Heart rate (HR) is modulated by sympathetic and parasympathetic systems via baroreflex mechanisms.
- Hyperpolarization-activated cyclic nucleotide-gated channels (HCN4) in the cardiac sinus node integrate these autonomic influences.
- HCN4 channels are critical for regulating heart rate and autonomic control.
Purpose of the Study:
- To investigate the effect of HCN4 blockade with ivabradine on HR and baroreflex regulation.
- To determine if ivabradine selectively affects HR regulation while preserving baroreflex control of muscle sympathetic nerve activity.
- To assess the impact of ivabradine on blood pressure regulation and baroreflex sensitivity.
Main Methods:
- A randomized crossover study involving 21 healthy men.
- Administration of ivabradine (2×7.5 mg) or placebo.
- Recording of electrocardiogram, blood pressure, and muscle sympathetic nerve activity during rest and pharmacological baroreflex testing.
Main Results:
- Ivabradine significantly reduced normalized HR (from 65.9±8.1 to 58.4±6.2 bpm, P<0.001).
- Blood pressure and muscle sympathetic nerve activity remained unaffected by ivabradine.
- Cardiac and sympathetic baroreflex gains were unchanged, as were blood pressure responses to vasoactive drugs.
- Ivabradine aggravated bradycardia during baroreflex loading (parasympathetic activation).
Conclusions:
- HCN4 blockade with ivabradine effectively reduces HR.
- Physiological regulation of HR, muscle sympathetic nerve activity, and baroreflex blood pressure buffering remain intact.
- Ivabradine has the potential to exacerbate bradycardia under conditions of increased parasympathetic tone.
Background:
Sympathetic and parasympathetic influences on heart rate (HR), which are governed by baroreflex mechanisms, are integrated at the cardiac sinus node through hyperpolarization-activated cyclic nucleotide-gated channels (HCN4). We hypothesized that HCN4 blockade with ivabradine selectively attenuates HR and baroreflex HR regulation, leaving baroreflex control of muscle sympathetic nerve activity intact.
Methods And Results:
We treated 21 healthy men with 2×7.5 mg ivabradine or placebo in a randomized crossover fashion. We recorded electrocardiogram, blood pressure, and muscle sympathetic nerve activity at rest and during pharmacological baroreflex testing. Ivabradine reduced normalized HR from 65.9±8.1 to 58.4±6.2 beats per minute (P<0.001) with unaffected blood pressure and muscle sympathetic nerve activity. On ivabradine, cardiac and sympathetic baroreflex gains and blood pressure responses to vasoactive drugs were unchanged. Ivabradine aggravated bradycardia during baroreflex loading.
Conclusions:
HCN4 blockade with ivabradine reduced HR, leaving physiological regulation of HR and muscle sympathetic nerve activity as well as baroreflex blood pressure buffering intact. Ivabradine could aggravate bradycardia during parasympathetic activation.
Clinical Trial Registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00865917.
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